This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The development of effective medications to treat cocaine addiction will depend on a better understanding of cocaine neuropharmacology. The current project utilized positron emission tomography (PET) neuroimaging techniques in nonhuman primates as a noninvasive approach to investigate cocaine-induced functional changes in central nervous system activity. The major emphasis has been on interactions between selective dopamine transporter (DAT) inhibitors and selective serotonin transporter (SERT) inhibitors on cocaine self-administration. We completed a series of studies to characterize the neuropharmacology of 3,4-methylenedioxymethamphetamine (MDMA), an abused amphetamine-type stimulant. The enantiomers of MDMA appear to have differential effects with (+)MDMA being primarily dopaminergic and (-)MDMA being primarily serotonergic. Interestingly, (+)MDMA was effective in reinstating extinguished amphetamine self-administration as a model of drug relapse. It also induced robust increases in extracellular dopamine, an effect shared by amphetamine and cocaine. In contrast, (-)MDMA was ineffective in reinstatement and in increasing dopamine. However, it was very effective in increasing plasma prolactin levels, an effect that is shared by serotonergic agonists. This may explain the unique pharmacology of MDMA in humans. We made significant progress in the development of fMRI in awake monkeys in order to characterize cocaine- and cue-induced brain activation at a neurocircuitry level. Collectively, the results have important implication concerning the development of substitute agonist pharmacotherapies to treat stimulant abuse.